MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Thanks for your questions about our research. My research group and I have a long-term interest in finding genes and mutations causing inherited retinal diseases. Our main focus is on retinitis pigmentosa (RP) and, more specifically, the autosomal dominant form of RP.

Inherited retinal diseases are progressive, degenerative diseases of the retina. Onset can be very early in life, even at birth, or much later in life. As the degeneration develops an affected person may first experienced limited loss of vision, progressing to severe loss of vision, ending, in many cases, in legal or complete blindness. About 300,000 Americans are affected by inherited retinal disease and 50% of these have RP. RP, like most hereditary conditions, can be inherited in an autosomal dominant, autosomal recessive or X-linked fashion.

One of the surprising, and in some sense, disturbing findings in studying retinitis pigmentosa is that mutations in many different genes can cause this disease. We now know that mutations in more than 80 genes can cause RP and thousands of different mutations have been found in these genes. With next-generations sequencing it is possible to find the cause of RP in from 50% to 80% of cases, depending on the underlying mode of inheritance.For example, in our research we can find the disease-causing mutation in about 75% of families with autosomal dominant RP. Needless to say, a primary aim of our research is to find the cause in the remaining 25%.

In looking for the cause of retinitis pigmentosa in the remaining 25%, that is, those in whom mutations were not detected by earlier methods, we found a potential dominant-acting mutation in the arrestin-1 gene (gene symbol “SAG”) using whole-genome sequencing. Molecular modeling suggests this mutation is damaging. This was unexpected because previously-reported mutations in this gene were associated with Oguchi disease, a recessive retinal disease with symptoms distinct from RP. On further testing our cohort of patients with autosomal dominant RP, we found this mutation in nearly 4% of families. Even more surprisingly, when we looked closely at the affected families, and worked with our collaborators to test other patients, we discovered that all of the families with the dominant-acting SAG mutation — 12 total — were of Hispanic origin. By interviewing informative family members we learned that these families have their roots in the Southwestern United States. Historically, the mutation may have arisen hundreds of years ago, consistent with genetic variation tracking with the mutation.

MedicalResearch.com: What should clinicians and patients take away from your report?

Response: There are several take-home lessons.

First, this emphasizes the point that different mutations in the same gene may cause different diseases, and some mutations may be recessive-acting and others may be dominant-acting. We have reported other examples of the dual nature of disease-causing mutations.

Second, this mutation alone accounts for nearly 4% of the unsolved dominant retinitis pigmentosa families in our study, moving us closer to the goal of finding the cause in 100% of families.

Finally, it is of historical interest that this mutation may have arisen during the early period of Spanish and Mexican land-grant settlements in North America and has been passed down for many generations in the original Hispanic families. This appears to be a classic “founder effect” mutation. The mutation traces to a common ancestor but contemporary families that share the mutation may not be aware of their relation to the other families.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: There are a number of questions regarding the origin and distribution of the mutation. Which other families share this mutation; is it unique to the Southwestern United States or is it also found in Mexico; is it found in Spain; are non-Hispanic families affected? We are currently trying to answer these questions. Then there are questions regarding the underlying pathogenic mechanism. Why does this particular mutation cause retinitis pigmentosa and why is it dominant-acting rather than recessive? Our collaborators are working on these questions. Then, of course, there is the primary aim of our research: what is the cause of RP in the remaining unsolved cases?

Finally, there is the fundamental question underlying all research on inherited retinal diseases: what can be done to provide treatments and cures? The complexity of RP and related diseases — the exceptional genetic heterogeneity — is at first glance disturbing because it suggests that causes and solutions must be found on a case-by-case basis. This could take decades. However, the good news is that genetic testing is close to the goal of finding the mutation or mutations in nearly all patients. This solves the “cause” part of complexity. Remarkably, there is also exceptional progress on the “solution” part. There are currently many potential treatments for RP and related diseases that have shown promise in animal models. Possibilities include gene therapy, small-molecule therapies, stem-cell therapies, and others. Many of these are already in clinical trials. For example, clinicaltrials.gov currently lists 120 registered studies for RP and several more for related conditions (July 2017). At present there are no registered studies relating to the SAG gene but we are optimistic that one or more of the possible treatments for other forms of RP will carry over to this specific, Hispanic form of retinal disease.

Disclosures: I am Vice-Chair of the Scientific Advisory Board of the Foundation Fighting Blindness, which supported this research, and I am on the Scientific Advisory Board of Applied Genetic Technologies Company (AGTC), which is developing therapies for inherited retinal diseases. Support was also provided by the William Stamps Farish Fund, the Hermann Eye Fund, and the National Institutes of Health.

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